Upper-room ultraviolet germicidal irradiation (UVGI) system is recently in the limelight as a potentially effective method to mitigate the risk of airborne virus infection in indoor environments. However, few studies quantitatively evaluated the relationship between ventilation effectiveness and virus disinfection performance of a UVGI system. The objective of this study is to investigate the effects of ventilation strategy on detailed airflow distributions and UVGI disinfection performance in an occupied classroom. Three-dimensional computational fluid dynamics (CFD) simulations were performed for representative cooling, heating, and ventilation scenarios. The results show that when the ventilation rate is 1.1 h−1 (the minimum ventilation rate based on ASHRAE 62.1), enhancing indoor air circulation with the mixing fan notably improves the UVGI disinfection performance, especially for cooling with displacement ventilation and all-air-heating conditions. However, increasing indoor air mixing yields negligible effect on the disinfection performance for forced-convection cooling condition. The results also reveal that regardless of indoor thermal condition, disinfection effectiveness of a UVGI system increases as ventilation effectiveness is close to unity. Moreover, when the room average air speed is >0.1 m/s, upper-room UVGI system could yield about 90% disinfection effect for the aerosol size of 1 μm–10 μm. The findings of this study imply that upper-room UVGI systems in indoor environments (i.e., classrooms, hospitals) should be designed considering ventilation strategy and occupancy conditions, especially for occupied buildings with insufficient air mixing throughout the space.